Skip to main content
eScholarship
Open Access Publications from the University of California

Discovery of a new class of highly potent inhibitors of acid ceramidase: Synthesis and structure-activity relationship (SAR)

  • Author(s): Pizzirani, D
  • Pagliuca, C
  • Realini, N
  • Branduardi, D
  • Bottegoni, G
  • Mor, M
  • Bertozzi, F
  • Scarpelli, R
  • Piomelli, D
  • Bandiera, T
  • et al.

Published Web Location

https://doi.org/10.1021/jm301879gCreative Commons Attribution 4.0 International Public License
Abstract

Acid ceramidase (AC) is an intracellular cysteine amidase that catalyzes the hydrolysis of the lipid messenger ceramide. By regulating ceramide levels in cells, AC may contribute to the regulation of cancer cell proliferation and senescence and to the response to cancer therapy. We recently identified the antitumoral agent carmofur (4a) as the first nanomolar inhibitor of intracellular AC activity (rat AC, IC50= 0.029 μM). In the present work, we expanded our initial structure-activity relationship (SAR) studies around 4a by synthesizing and testing a series of 2,4-dioxopyrimidine-1- carboxamides. Our investigations provided a first elucidation of the structural features of uracil derivatives that are critical for AC inhibition and led us to identify the first single-digit nanomolar inhibitors of this enzyme. The present results confirm that substituted 2,4-dioxopyrimidine-1-carboxamides are a novel class of potent inhibitors of AC. Selected compounds of this class may represent useful probes to further characterize the functional roles of AC. © 2013 American Chemical Society.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Main Content
Current View